Mitochondrial Dysfunction in C. elegans Activates Mitochondrial Relocalization and Nuclear Hormone Receptor-Dependent Detoxification Genes

Summary In Caenorhabditis elegans , mitochondrial dysfunction caused by mutation or toxins activates programs of detoxification and immune response. A genetic screen for mutations that constitutively induce C. elegans mitochondrial defense revealed reduction-of-function mutations in the mitochondrial chaperone hsp-6 /mtHSP70 and gain-of-function mutations in the Mediator component mdt-15 /MED15. The activation of detoxification and immune responses is transcriptionally mediated by mdt-15 /MED15 and nuclear hormone receptor nhr-45 . Mitochondrial dysfunction triggers redistribution of intestinal mitochondria, which requires the mitochondrial Rho GTPase miro-1 and its adaptor trak-1 /TRAK1, but not nhr-45 -regulated responses. Disabling the mdt-15 / nhr-45 pathway renders animals more susceptible to a mitochondrial toxin or pathogenic Pseudomonas aeruginosa but paradoxically improves health and extends lifespan in animals with mitochondrial dysfunction caused by a mutation. Thus, some of the health deficits in mitochondrial disorders may be caused by the ineffective activation of detoxification and immune responses, which may be inhibited to improve health.